The incidence of cardiovascular disease (CVD) continues to rise. While the causes are multiple, protein and lipid derived Advanced Glycoxidation Endproducts (AGE) are key contributors to CVD. AGE levels are high in both diabetes and aging, and lead to CVD because they cause a pro-oxidant and pro-inflammatory injury. Thus, the prevention of AGE accumulation and its removal and detoxification are of therapeutic interest. The sources of excess AGE are two-fold, endogenous formation by Maillard reaction and accumulation from exogenous sources (such as the western diet). AGEs bind to a number of cell receptors (ACER). AGER1, could be considered to be "protective", since it mediates AGE removal and detoxification without inducing an intracellular inflammatory response. Other AGERs, including RAGE, can induce an inflammatory and oxidative stress (OS) response. The balance between these different receptor-mediated responses may be key to AGE-toxicity and the resultant CVD. One mechanism underlying AGE accumulation may be decreased removal, possibly due to low AGER1 expression. In fact, we found low AGER1 levels in certain high AGE states. We hypothesize that a reduction of AGER1 function, results in reduced AGE uptake and destruction as well as impairment of its intracellular anti-inflammatory actions. Since AGER1 mediates AGE uptake and exerts an inhibitory effect on the pro-oxidant, inflammatory effects of AGE, low expression or abnormal function could have two adverse effects: 1) decreased uptake and degradation of AGE, leading to high circulating and tissue levels, and 2) unopposed induction of an intracellular pro-oxidant/inflammatory response induced via the RAGE receptor, promoting CVD. The mechanism by which the AGER1 carries out these two functions is the subject of this proposal using a combination of in vitro and in vivo approaches, including our new AGER1-transgenic mouse. Aim 1: AGER1-dependent AGE-removal and activation- inhibition, under normal and "high oxidant stress" conditions: In vitro studies. Aim 2: AGER1-dependent AGE removal and activation-inhibition under conditions of variable glycoxidant stress: In vivo studies. Aim 3: In vivo assessment of AGER1 function in AGER1-transgenic mice. The elucidation of AGER1 mechanisms, which influence the regulation of AGE clearance (positively) and/or the pro-OS, inflammatory pathways (negatively) may generate new therapeutic targets against human vascular disease.